Abstract

The central goal of cancer immunotherapy is to control tumors through the mobilization
of the patient's immune system. Vaccines targeting the Her2/neu proto-oncogene have been tested with some early encouraging responses in breast cancer.
However, a more effective set of vaccines targeting specific immune cell subtypes
may provide a more potent means to stimulate anti-tumor immunity. Dendritic cell-specific
antibodies fused with the Her2/neu protein proved effective at generating immune responses in preclinical models. Importantly,
only low amounts of protein vaccine were required to generate this response, which
has potentially significant implications for the future clinical development of Her2/neu-targeted vaccines and other vaccine targets.

Editorial

Despite significant advances in the treatment of Her2/neu-overexpressing breast cancer in the last few decades, the majority of patients with
meta static Her2/neu+ tumors ultimately succumb to their disease. Moreover, Her2/neu proto-oncogene has generally been associated with a poor clinical outcome; however,
the overexpression of this cell surface growth factor receptor also provides a target
that can be exploited for immunotherapeutics. Her2/neu-specific vaccines have been tested with a further refinement in the potential effectiveness
of a protein vaccine described in a paper in the previous issue of Breast Cancer Research [1]. Moreover, support for the immunotherapy approach comes from the fact that monoclonal
antibody therapy (trastuzumab) improves survival in both the adjuvant [2,3] and metastatic [4] setting. However, despite improvements in clinical outcome, metastatic breast cancer
remains incurable and new treatments are needed.

The adoptive transfer of immune effector molecules (including monoclonal antibodies)
and cells is termed passive vaccination. The success of this approach is likely dependent
upon the persistence of the molecule/cell and its ability to engage the particular
immunological process that results in a sufficient anti-tumor response. However, achieving
sustained levels of immune effector molecules and cells in the patient is difficult
and generally requires large amounts of protein or cells to be administered over a
prolonged period of time.

Active vaccination refers to the process of stimulating the patient's own immune system
to drive an anti-tumor response. The major attraction of this approach is the potential
to generate immunological memory, which may protect against relapsing tumors. Preclinical
breast cancer vaccine strategies targeting Her2/neu and other breast cancer antigens established the proof of principle of the approach
[5,6]. Encouragingly, early-phase clinical studies using peptides derived from the Her2/neu protein (E75 and GP2) have shown evidence of immunological responses [7,8], and a more recent study suggests a potential clinical benefit in subsets of patients
treated with the E75 peptide vaccine [9]. However, large phase III clinical trials of cancer vaccines that target solid tumors
have largely failed to deliver major clinical benefits, despite the induction of humoral
and cellular immune responses, indicating that improvements in vaccine design are
clearly required [10].

At the heart of the immune system resides the dendritic cell (DC). Pivotal studies
led by Ralph Steinman identified the DC as the key player involved with controlling
the immune response. (Quite rightly, he was awarded a Nobel Prize for his work although
he had passed away shortly before the names of the Prize winners were announced last
year.) These studies of the biology of DCs have led to the identification of target
molecules that may be exploited in vaccine design, including the C-type multilectin
DEC205, which is expressed at high levels on lymphoid DCs. Proteins bound by DEC205
are internalized, proteolysed, and presented in the context of major histocompatibility
complex class II proteins. Previous studies from the Steinman group exploited a DEC205
specific monoclonal antibody to deliver the HIV and Epstein-Barr virus antigens to
DCs, resulting in specific viral immune responses in mice, macaques, and human volunteers
[11,12]. However, targeting antigen delivery to DEC205+ DCs alone is insufficient to fully mature DCs and thereby stimulate an immune response;
DC maturation by the co-administration of agents such as polyinosinic:polycytidylic
acid (poly I:C) with the DEC205 antibody-antigen fusion drives enhanced CD4+ T-cell vaccine-driven responses [13].

These studies provide the rationale supporting a paper that was published by the Steinman
group in the previous issue of Breast Cancer Research and details the construction and activity of a fusion protein consisting of the anti
DEC 205 antibody linked to the extracellular domain of Her2/neu [1]. In that study, Wang and colleagues confirm that mice vaccinated with the DEC205-Her2
fusion protein in combination with poly I:C develop strong Her2-specific antibody
and CD4+ T-cell responses while the fusion protein also drove antigen-specific CD8+ T-cell responses as a result of cross-priming [1]. The critical result in that study was the relative potency of the fusion protein;
as little as 2.7 μg of Her2/neu protein was sufficient to induce a tumor-protective effect [1]. This observation strongly supports the further development of the DEC205-Her2 fusion
protein vaccine and also suggests that less vaccine would be required for clinical
study with implicit potential cost reductions.

However, the road to a successful cancer vaccine is long. Inducing vaccine responses
in the mouse is an important prerequisite to confirm that the basic vaccine is functional.
Human tumor antigens such as Her2/neu are not present in the mouse and, consequently, are not subject to immune regulation
as would be expected in the patient with breast cancer. Breaking immunological tolerance
is essential to permit immune responses against 'self' tumor-associated antigens such
as Her2/neu. Vaccines targeting self-antigens in the mouse confirm that immunological tolerance
blunts vaccine-induced T-cell responses [14]. Consequently, testing the potency of the DEC205-Her2 fusion protein in the Her2/neu transgenic model would be an important next stage to determine the potency of this
vaccine in breaking immunological tolerance. However, Her2/neu-specific T-cell responses and antibody responses have been documented in patients
with Her2/neu+ tumors [15], and patients treated with peptide-based vaccines have mounted HER2/neu-specific immune responses [7,9], implying that overcoming immunological regulation of Her2/neu in patients with breast cancer is feasible.

Mouse preclinical model systems are limited in their relevance to the human situation.
The successful development of the vaccine will be reliant upon optimizing the DC maturation
adjuvant to be used in conjunction with the DEC205-Her2 protein and will also have
to consider how the patient's immune system and tumor are affected by previous therapies.
There is evidence that the antitumor immune response can be either enhanced or abrogated
by altering the schedule of different chemotherapeutic agents. It may therefore be
possible to enhance the anti-tumor immune response induced by vaccine therapy by optimizing
the delivery of standard therapies [16]. Overall, the identification of a potent protein-based Her2/neu vaccine provides a refinement of vaccine development and warrants further investigation.